The primary objective was to investigate the association between partial pressure of carbon dioxide (PaCO₂) change after extracorporeal membrane oxygenation (ECMO) initiation and neurologic outcome in neonates treated for respiratory failure. A retrospective analysis of the Extracorporeal Life Support Organization (ELSO) database including newborns supported by ECMO for respiratory indication during 2015–2020. The closest Pre-ECMO (Pre-ECMO PaCO₂) and at 24 hours after ECMO initiation (H24 PaCO₂) PaCO₂ values allowed to calculate the relative change in PaCO₂ (Rel Δ PaCO₂ = [H24 PaCO₂ – Pre-ECMO PaCO₂]/Pre-ECMO PaCO₂). The primary outcome was the onset of any acute neurologic event (ANE), defined as cerebral bleeding, ischemic stroke, clinical or electrical seizure, or brain death during ECMO. We included 3,583 newborns (median age 1 day [interquartile range {IQR}, 1–3], median weight 3.2 kg [IQR, 2.8–3.6]) from 198 ELSO centers. The median Rel Δ PaCO₂ value was −29.9% [IQR, −46.2 to −8.5]. Six hundred nine (17%) of them had ANE (405 cerebral bleedings, 111 ischemic strokes, 225 seizures, and 6 brain deaths). Patients with a decrease of PaCO₂ > 50% were more likely to develop ANE than others (odds ratio [OR] 1.78, 95% confidence interval [CI], 1.31–2.42, p < 0.001). This was still observed after adjustment for all clinically relevant confounding factors (adjusted OR 1.94, 95% CI, 1.29–2.92, p = 0.001). A significant decrease in PaCO₂ after ECMO start is associated with ANE among neonates requiring ECMO for respiratory failure. Cautious PaCO₂ decrease should be considered after start of ECMO therapy.